Several antipsychotic agents, of which clozapine is prototypical, have been classified as atypical antipsychotics primarily on the basis of the low incidence of extrapyramidal side effects (EPS) and the minimal effect on prolactin (PRL) secretion in man. Recent data from a multicenter clinical trial of clozapine are suggestive that clozapine is more efficacious than typical neuroleptics in diminishing positive and negative symptoms in treatment-resistant schizophrenics. Hence, it can be hypothesized that clozapine may have additional mechanisms of action relevant to its anti-psychotic actions. These actions may also contribute to its unique effects on EPS and PRL secretion. We have obtained data from neuroendocrine studies in the rat that indicate qualitative differences in the mechanisms of action of typical and atypical antipsychotics. In particular, it has been found that atypical antipsychotics, in contrast to typical antipsychotics, produce: 1) a short-lived increase in serum PRL concentrations, 2) a marked increase in serum corticosterone concentrations, and 3) an activation of tuberoinfundibular dopamine (TIDA) neurons. The overall goal of the proposed studies is to elucidate the mechanisms which mediate these unique neuroendocrine responses to atypical neuroleptics and to ascertain the extent to which the neuronal substrates through which clozapine acts on TIDA neurons are similar to those through which this antipsychotic acts on mesolimbic-mesocortical DA neurons. It is proposed to test the hypothesis that clozapine activates TIDA neurons through an interaction with DA1, 5-HT2, muscarinic and/or 1-adrenergic receptors. The hypothesis that neurotensin or corticotropin releasing factor is involved in the atypical antipsychotic-induced activation of TIDA neurons also will be examined. These studies will be conducted in rats in which the activity of TIDA and mesolimbic-neurocortical DA neurons will be assessed through the biochemical determination of the rate of accumulation of the DA precursor, DOPA, after inhibition of DOPA decarboxylase and DOPAC concentrations in the median eminence and medial prefrontal cortex. The studies proposed herein focus on the mechanisms through which the actions of atypical antipsychotics can be differentiated from those of typical neuroleptics. It is suggested that the results of these studies will provide some insight into the mechanism which determine the efficacy and low EPS producing liability of clozapine with regard to the treatment of schizophrenia.